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Gut microbiome alterations in children with AIS

Abstract
The etiology of adolescent idiopathic scoliosis (AIS), the most common rotational deformity of the spine, is still unclear. Emerging evidence suggests that gut microbiota dysbiosis influences musculoskeletal diseases such as arthritis and osteoporosis. However, the alterations of the fecal microbiome in AIS remain unknown. Thus, the current study was conducted to explore the gut microbiota compositions of Chinese AIS patients. Microbiota communities in the feces of 51 AIS patients and 34 age- and sex-matched healthy individuals were investigated using 16S rRNA sequencing. Meanwhile, the changes in the plasma proteome were detected using tandem mass tag (TMT) labeling coupled with liquid chromatography-mass spectrometry (LC-MS). The relationship between gut microbiota and AIS clinical characteristics as well as the correlation between gut microbiota and the changes in plasma proteins were analyzed. The structure of the gut microbiota differed between the AIS and healthy groups, however, the richness was similar. The genera Prevotella, Gelria, and Desulfovibrio were enriched in the feces of AIS patients. In contrast, the abundance of Parasutterella, Tyzzerella, and Phascolarctobacterium was decreased in the AIS group. More remarkably, a positive correlation between the abundance of the fecal genera Prevotella and the Cobb angles of the AIS patients was observed. Moreover, the major differential plasma proteins related to AIS were Fibronectin 1 (FN1), voltage-dependent anion channel 1 (VDAC1), Ras homolog family member A (RHOA), and AHNAK nucleoprotein (AHNAK). Additionally, the positive correlations between fecal Prevotella and the expression of host plasma FN1 as well as the negative relationships between fecal Prevotella and the expression of host VDAC1 and AHNAK were confirmed. Elucidating these differences in the gut microbiota will provide a foundation to improve our understanding of the pathogenesis of AIS and to support potential therapeutic options based on modifying the gut microbiota.

Discussion
Nutrition has already been implicated in scoliosis due to rickets, and worldwide there has been an anecdotal association between poor nutrition and IS. In rural South America, Risser is reported to have observed that a large portion of the IS patients were malnourished and consumed more sugar and flour than normal children. Frederich noted the poor nutritional status of European patients, while Stearns found that American IS patients consumed too many carbohydrates and too little protein.

These observations are supported by two recent studies, one in the Soviet Union and the other in the United States. The Soviet study found that the incidence of IS was 4 times higher in undernourished children than the population of children at large, while the United States study found that IS patients were picky eaters who consumed twice the amount of candy and soda as their unaffected contemporaries. it is noteworthy that the observers who mentioned any particular dietary anomaly, all noted the larger than average consumption of carbohydrates: in particular, simple carbohydrates.

Study:Role of Gut Microbiota in Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a systemic autoimmune disease, caused by both genetic and environmental factors. Recently, investigators have focused on the gut microbiota, which is thought to be an environmental agent affecting the development of RA. Here we review the evidence from animal and human studies that supports the role of the gut microbiota in RA. We and others have demonstrated that the abundance of Prevotella copri is increased in some early RA. We have also used gnotobiotic experiments to show that dysbiosis in RA patients contributed to the development of Th17 cell-dependent arthritis in intestinal microbiota-humanized SKG mice. On the other hand, Prevotella histicola from human gut microbiota suppressed the development of arthritis. In summary, Prevotella species are involved in the pathogenesis of arthritis.

A recent paper in the journal Nature discusses experiments that provide a link between a certain gut bacteria, diet, and osteomyeltis (an autoinflammatory bone disease). Osteomyelitis occurs when there is a bacterial infection of the bone marrow. It is often treated with antibiotics but sometimes surgery and amputation are necessary.

In the study, the researchers induced osteomyelitis in a group of mice. They then gave half the mice high fat diets and half the mice low fat diets. They discovered that the mice eating the high fat diets were protected from osteomyelitis and showed little bone inflammation, while those eating a low fat diet developed the disease.

The discovery that diet could alter the progression of the disease led the researchers to investigate the microbiome of these mice. The mice with low fat diets had higher amounts of Prevotella and lower amounts of Lactobacillus when compared to normal mice. The reverse was true for the high fat diet mice, they had much less Prevotella and much more Lactobacillus in their guts, which better represents the composition in normal mice.

To further investigate if Prevotella may be causing the disease, the researchers gave antibiotics to the low fat diet mice, which destroyed the Prevotella population, and decreased the symptoms of the disease.

Finally, the researchers performed microbiome transplants into germ-free mice that were susceptible for osteomyeltis. Any germ-free mouse that received a transplant high in Prevotella and then was fed a low fat diet developed the disease. However, any mouse that received a transplant that was low in Prevotella, even if that mouse was on a low fat diet, did not develop the disease.

These results show that dietary intake can alter the microbiome and greatly influence osteomyelitis outcomes.

The microbiota plays a central role in human health and disease by shaping immune development, immune responses and metabolism, and by protecting from invading pathogens. Technical advances that allow comprehensive characterization of microbial communities by genetic sequencing have sparked the hunt for disease-modulating bacteria. Emerging studies in humans have linked the increased abundance of Prevotella species at mucosal sites to localized and systemic disease, including periodontitis, bacterial vaginosis, rheumatoid arthritis, metabolic disorders and low-grade systemic inflammation. Intriguingly, Prevotella abundance is reduced within the lung microbiota of patients with asthma and chronic obstructive pulmonary disease. Increased Prevotella abundance is associated with augmented T helper type 17 (Th17) -mediated mucosal inflammation, which is in line with the marked capacity of Prevotella in driving Th17 immune responses in vitro. Studies indicate that Prevotella predominantly activate Toll-like receptor 2, leading to production of Th17-polarizing cytokines by antigen-presenting cells, including interleukin-23 (IL-23) and IL-1. Furthermore, Prevotella stimulate epithelial cells to produce IL-8, IL-6 and CCL20, which can promote mucosal Th17 immune responses and neutrophil recruitment. Prevotella-mediated mucosal inflammation leads to systemic dissemination of inflammatory mediators, bacteria and bacterial products, which in turn may affect systemic disease outcomes. Studies in mice support a causal role of Prevotella as colonization experiments promote clinical and inflammatory features of human disease. When compared with strict commensal bacteria, Prevotella exhibit increased inflammatory properties, as demonstrated by augmented release of inflammatory mediators from immune cells and various stromal cells. These findings indicate that some Prevotella strains may be clinically important pathobionts that can participate in human disease by promoting chronic inflammation.

You take a look at a few of Dr Boachies extreme spine patients in Africa, and that kind of makes you wonder about diet, and its relationship to scoliosis.....

Thanks for posting all the studies...

Ed

Ed I think the prevalence of large curves is inversely proportional to the availability of fusion. So we see many large curves in African countries, some in Canada, and virtually none in the US. In the US we simply don't allow kids who are on the radar to progress that much. There is medical consensus on fusing curves in kids before they get that big.

Sharon, mother of identical twin girls with scoliosis

No island of sanity.

Question: What do you call alternative medicine that works?Answer: Medicine

You take a look at a few of Dr Boachies extreme spine patients in Africa, and that kind of makes you wonder about diet, and its relationship to scoliosis.....

Thanks for posting all the studies...

Ed

Yup who knows which harmful agents are loose in the environment of Africa and other parts of the world.

When 63% of the people that suffer from Hyper-IgE syndrome which is characterized by chronic infection also suffer from Scoliosis that's really eye opening. I had never heard that mentioned until the Zebrafish study came out.

An infection or harmful inflammation was always the safest bet because researchers knew that Polio could result in spinal deformity at least 100 years ago. It was a safe, well understood, scientifically proven concept. Furthermore inflammation is connected to almost every disease. Google just about any disease and the word "inflammation" and you'll get pages of results.

Ed I think the prevalence of large curves is inversely proportional to the availability of fusion. So we see many large curves in African countries, some in Canada, and virtually none in the US. In the US we simply don't allow kids who are on the radar to progress that much. There is medical consensus on fusing curves in kids before they get that big.

I guess this is a partially true statement. We do have the occasional extreme spine patient show up here every once in a while.... Either they have been misled, or they are hiding from fear....

Right now there is a member here that is doing "THE" hardest recovery....circumstances that I have never seen before. This person is in the US.

This surgery and video was done in 2006. It gave me the courage to continue with my decision, I watched it a dozen times.

Knowing that there are survivors that make it through the most difficult of spine cases is of value. Its hard for us to watch these things, but it helps us understand and helps others understand what happens in the operating room. I knew I could get this done after seeing this.

Dr Boachie worked at HSS in New York for many years, but he had to go home and do something. Surgeons become surgeons because they want to help others. Its not about the money, its about helping others. http://www.orthofocos.org/

That is a tough video to watch and I'm not talking about the actual surgery. Those poor kids.

This at the 2:47 mark may explain why Scoliosis is so severe in Africa.
YouTube: Juma Jenda (2:47)

The FOCOS team treats some of the worst spinal deformities in the world. Many cases of Scoliosis result from childhood infections like Tuberculosis or Polio that actually penetrate the spinal vertebrae and cause them to swell and sometimes fuse together.

I did not know that Tuberculosis caused Scoliosis. But from that video those infections look like they cause the most severe type.

Yeah....Maybe its a reminder of how lucky we are to have what we have......We kind of overlook these sorts of things, and truly realize when we do leave the US. I always kiss the ground (regardless of pathogens) when I get back home from travelling overseas.

There are severe cases all over the world. Years ago, it seemed like there were a lot of large kyphosis cases in England on the SSO forum. Its hard to pinpoint a specific pathogen to each case, and you cant really do that if they are congenital. The Cotrel White book MRI studies in Hong Kong of the inner ear and cord malformations were pretty conclusive...I posted in the research section a few months ago. Left inner ear, right thoracic. Those studies make one wonder if we are all congenital scoliosis patients. There has to be a cause even if its before the curve. You can have a cause and a delay which presents another problem that needs to be figured out.

A very high percentage of males over age 50 have prostate cancer.....there is some reason why it acts so slowly. The glove check really doesn't cut the mustard. It makes for some great jokes, but essentially its like catching a scoli with a 50 degree Cobb. A little late.

I am currently having problems with my ear or ears. Dizziness, and now once again the dreaded vertigo spells. The twilight zone. I was diagnosed with Viral Labyrinthitis in 1992. There is not much they can do.....Vertigo is a really hard thing to deal with sometimes all I can do is hang on. It wears you down. I'm not driving. I had the flu in October. https://en.wikipedia.org/wiki/Labyrinthitis

There are severe cases all over the world. Years ago, it seemed like there were a lot of large kyphosis cases in England on the SSO forum.

The reason there are large kyphoses in the UK and why we have children with large scoliosis in Canada are directly attributable to the wait times. Elias in Canada had a huge curve and STILL was never scheduled. If Shriners in the US didn't take him who knows how big it would get. And Canada is a first world country. Multiply that problem for African counties where the wait time is approaching infinity if it isn't already infinite for most kids.

Idiopathic scoliosis is about 2-3% all over the world. Therefore the INCIDENCE of IS in the US and UK and Africa is probably similar with the possible exception of the UK and that area of the world where there seems to be an additional genetic predisposition over and above the 2-3% genetic predisposition.

Given similar incidence, the PREVALENCE of large curves is controlled by availability of treatment. Knowing the availability we can accurately predict that there will be more large curves in the UK than in the US and more large curves in African compared to both the US and UK. And that is what we see.

For non-idiopathic cases like those due to polio, the incidence and prevalence are controlled by the incidence of polio virus or other viruses or bacteria. For countries that don't have vaccination programs, the incidence and prevalence of scoliosis due to these causes and not idiopathic is whatever it is. It may or may not be higher than the 2-3% for IS all over the world. I hope it much lower. We have eradicated small pox worldwide so I think there must be worldwide vaccination programs for other diseases. If so, most of the scolioses in Africa are probably still idiopathic scoliosis, many/most of which go unfused and so become large.

Last edited by Pooka1; 12-18-2018 at 08:26 AM.

Sharon, mother of identical twin girls with scoliosis

No island of sanity.

Question: What do you call alternative medicine that works?Answer: Medicine

Idiopathic scoliosis is about 2-3% all over the world. Therefore the INCIDENCE of IS in the US and UK and Africa is probably similar with the possible exception of the UK and that area of the world where there seems to be an additional genetic predisposition over and above the 2-3% genetic predisposition.

Hypothesis 1) The population in the British Isles selected for genes that cause potentially fatal spinal deformities in children.
Hypothesis 2) Low levels of Vitamin D.

Taking into account the recent barrage of studies that implicate inflammation I know which way I'd bet.

Our retrospective study compared vitamin-D levels in 229 patients with adolescent idiopathic scoliosis (AIS) and 389 age-matched controls, and evaluated the correlation between vitamin-D levels and sex, Cobb's angle, and serum levels of calcium (Ca), phosphorus, and alkaline phosphatase in the AIS group. Vitamin-D levels were lower in the AIS group, with no sex-specific effects, indicative of a possible vitamin-D resistance in AIS. Vitamin-D levels correlated positively with Ca levels and negatively with Cobb's angle, indicative of a possible role of vitamin D in the etiopathogenesis of AIS. Patients with AIS should be monitored for vitamin-D deficiency/insufficiency.

Beyond its critical function in calcium homeostasis, vitamin D has recently been found to play an important role in the modulation of the immune/inflammation system via regulating the production of inflammatory cytokines and inhibiting the proliferation of proinflammatory cells, both of which are crucial for the pathogenesis of inflammatory diseases. Several studies have associated lower vitamin D status with increased risk and unfavorable outcome of acute infections. Vitamin D supplementation bolsters clinical responses to acute infection. Moreover, chronic inflammatory diseases, such as atherosclerosis-related cardiovascular disease, asthma, inflammatory bowel disease, chronic kidney disease, nonalcoholic fatty liver disease, and others, tend to have lower vitamin D status, which may play a pleiotropic role in the pathogenesis of the diseases. In this article, we review recent epidemiological and interventional studies of vitamin D in various inflammatory diseases. The potential mechanisms of vitamin D in regulating immune/inflammatory responses in inflammatory diseases are also discussed.